The increasing prevalence of obesity, type 2 diabetes (T2D), and metabolic syndrome are among the most challenging and costly medical disorders of modern society, heightening the need for new strategies for improving glycemic control and prevention of associated co-morbidities. Hyperglycemia is the primary cause of the many complications of diabetes, but the development of more effect therapeutic regimens has been hampered by our limited understanding of the mechanisms of diabetes pathogenesis. Glucose effectiveness (GE), the ability of glucose to promote its own disposal independently of insulin, makes a contribution approximately equal to that of insulin in glucose disposal, however the mechanisms that regulate GE remain poorly understood. As GE is markedly impaired in obesity and T2D, strategies based on increasing GE have important therapeutic potential. Our recent finding that the central action of the gastrointestinal hormone Fibroblast growth factor-19 (FGF19) lowers blood glucose by rapidly and potently increasing GE supports evidence of a brain-centered glucoregulatory system (BCGS) that works cooperatively with pancreatic islets to regulate blood glucose. A role for the BCGS has also been implicated for the anti-diabetic effect of activation of the intestine-brain-liver (IBL) axis by intestinal nutrients and bariatric surgery We propose to use state-of- the art surgical approaches in combination with sophisticated FSIGT/Minimal Modeling, metabolomics and tracer dilution hyperglycemic clamp techniques to determine if a centrally mediated increase of GE contributes to the ability of either activation of the IBL axis or bariatric surgery (or both) to improve glucose homeostasis. In addition, we will characterize the ability of specific macronutrients infused into the intestinal lumen to regulate te secretion FGF15, the rodent homologue of human FGF19. Ultimately, these studies are anticipated to establish a physiological for GE in the lowering of blood gluocose by activation of the IBL axis by intestinal nutrients and bariatric surgery glucose via a mechanism involving the BCGS. This outcome would constitute a significant advance of our understanding of glucose homeostasis and suggest that improved management of T2D may be achievable through interventions that increase GE to complement islet-centered therapies that would not require surgical disruption of the gastrointestinal tract. The proposed project unites the clinical gastroenterology, hepatology and nutrition interests and research skills of the applicant as well as the considerable multi-disciplinary resources of the institution to advance understanding of the pathophysiology of diabetes and open the door for future advances in diabetes treatment.